Scenario 1 Initiation

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Scenario 1 Initiation Carcinogens are
mutagens Ras mutations
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Vincent
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Epidemiology
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Percival Pott Father of Epidemiology 1774
Linked soot with scrotal and nasal cancers in
chimney sweeps First link between environment
and cancer.
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Polycyclic aromatic hydrocarbons as found in
cigarette smoke are powerful carcinogens
e.g MCA Methyl cholanthrene DMBA Dimethyl
benzanthracene Meet them again later
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Animal experiments
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Initiation of tumours CARCINOGENESIS
Chemicals tested by painting on skin of mice or
rats
Active substances CARCINOGENS
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Historic problem for Somatic Mutation Hypothesis
Carcinogens are un-reactive with DNA, therefore
are not Mutagens
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Ames Test
Bacteria leaky and DNA-repair deficient
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His- to His revertants give colonies
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Notorious PAH carcinogens chemically un-reactive
with DNA therefore not mutagenic on bacteria
However in mammals are substrates for
de-toxifying enzymes e.g liver microsomal P450
oxidase
Oxidation converts PAHs to electrophilic
reagents which form adducts with DNA which
generate mutations after replication
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Enzymic oxidation converts PAHs to electrophilic
reagents which form adducts with DNA These
generate mutations after replication
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Not all environmental effectsare genotoxic, e.g.
also
Wounding and Tumour promotion

• Tumour promoter
• Phorbol Myristate Acetate (PMA)
• activator of Protein Kinase C

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Tumour promotion may expand pool
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Tumour Initiation summarised Epidemiology
highlighted environmental carcinogens These are
mutagens (Ames test) They induce tumours in
animals, aided by stimuli to cell proliferation
or differentiation
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Ras (gene from Rat sarcoma) important because
1/4 all human tumours have ras mutations
In animal models ras mutations initiate tumours
Gene product p21ras member of large family of
small cytoplasmic G-proteins involved in signal
switching. Also - related to tubulin
Signalling pathway later
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Most oncogenic ras mutations inactivate the
GTP-ase thus locking the p21 switch into the ON
state Potential for confusion Inactivating the
GTP-ase activates P21 as oncogene
Two hotspots for these mutations Residue 12
(glycine, any other aa. kills GTPase) Residue 61
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Polycyclic aromatic hydrocarbons as found in
cigarette smoke are powerful carcinogens
e.g MCA Methyl cholanthrene DMBA Dimethyl
benzanthracene Meet them again later
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Ras mutations in tumour initiation
Base change in ras sequenced from tumours Is
specific to the identity of the
carcinogen Experimental rat mammary gland
carcinomas Carcinogen NMU tumours have G
to A in codon 12 Carcinogen DMBA tumours
have A to T in codon 61
Experimental induction of mouse skin
carcinomas Carcinogen MCA tumours have G
to T in codon 12
(Same found in lung tumours of human smokers)
This is evidence that these are initiating events